Abstracts

Rationale: Carbamazepine (CBZ) is a commonly prescribed oral antiepileptic drug (AED) in the United States and other countries. Situations may arise where patients are unable to take oral CBZ due to illness, injury, surgery, or changes in mental status. Thus, an intravenous (IV) formulation of CBZ was developed for this patient population. Results from a recent clinical study showed that IV CBZ infused at 70% of the total daily dose (TDD) every 6 hours was bioequivalent to oral CBZ. Further evaluations using a pharmacokinetic (PK) model were done to assess the bioequivalence of oral CBZ to IV CBZ infused at 75% and 80% of the oral TDD. Methods: PK data from patients who received an IV CBZ infusion at a 70% dose conversion from the oral formulation were used in these analyses. CBZ plasma concentration profiles and parameters were simulated and evaluated (Phoenix WinNonLin v6.3: Pharsight, Cary, NC, USA) for both oral CBZ and IV CBZ infused for 15- or 30-minutes every 6 hours at either 75% or 80% of the total daily oral dose. Minimum, maximum, and average plasma concentrations (C_min, C_max, C_avg, respectively), area under the time-concentration curve from 0-24 hours (AUC_0-24), and partial AUC (pAUC) at 0-2, 2-4, 4-6, and 0-6 hours were determined. Bioequivalence between oral and IV CBZ was declared if the 90% confidence intervals (CI) of the ratio of geometric least square means for the PK parameters were within the 80-125% range. Results: Simulation of IV CBZ infused over 15 minutes every 6 hours at 70% of the oral TDD was similar to observed values and validated the predictive performance of this PK model. With a 15‑minute infusion rate, predicted steady-state PK estimates of C_min and C_avg were within the 90% CI, though the predicted C_max was above the CI upper limit for all IV CBZ dose conversion groups. Similarly, for IV CBZ infused at the 30-minute rate at both 75% and 80% of the oral TDD, most predicted steady-state PK estimates of C_min and C_avg were within the 90% CI, and predicted C_max values were above the upper CI limit. AUC predictions for IV CBZ at a 15-minute infusion rate appeared to be better than the 30-minute infusion rate, as more pAUC values were outside of the 90% CI with simulations of IV CBZ infused over 30 minutes. Conclusions: Based on PK simulations, IV CBZ infused at a 15-minute rate every 6 hours at 75% or 80% of the oral TDD was bioequivalent to oral CBZ for C_min, C_avg, AUC, but not for C_max. Comparing 15- and 30-minute infusion rates, IV CBZ infused over 15 minutes every 6 hours appeared to better meet the 90% CI criteria for bioequivalence to the oral formulation based on pAUCs. Thus, IV CBZ infused over 15 minutes at either dose conversion may provide an acceptable alternative treatment option.